J Cancer Allied Spec 2020;6(1):1 Case Report

Pulmonary Haemosiderosis Secondary to Hereditary Haemochromatosis; a Case Report

Waqas Jehangir1, Alexander D. Karabachev2, Elvira R. Umyarova1 1Department of Hematology and Oncology, University of Vermont Medical Center, Burlington, Vermont, United States, 2Department of Medicine, University of Vermont, Larner College of Medicine, Burlington, Vermont, United States Received: 01 September 2019/Accepted: 29 November 2019

OPEN ACCESS Abstract Correspondence: Waqas Jehangir, Department of Introduction: Hereditary haemochromatosis (HH) is an autosomal recessive Hematology and Oncology, disease of increased intestinal absorption of iron, leading to accumulation University of Vermont Medical in tissues which may progress to organ damage, most commonly in the Center, 111 Colchester Ave, liver. Iron deposition in the liver can lead to cirrhosis and hepatocellular Burlington, Vermont 17822, United States. carcinoma. Other common manifestations of haemochromatosis include Email: [email protected] diabetes, bronzing of the skin, arthropathy and cardiomyopathy. Here, Citation: Jehangir W, we describe a case of pulmonary haemosiderosis secondary to HH. Karabachev AD, Umyarova ER. Case Description: A 49-year-old male with no medical history or family Pulmonary haemosiderosis secondary to hereditary history of iron overload presented with fatigue, shortness of breath and haemochromatosis; a case chest pain after a recent finding of elevated ferritin. The patient was found report. J Cancer Allied to have biallelic C282Y mutations of the human homeostatic iron regulator Spec [Internet]. 2020 Jan.6; protein (HFE) protein and after further workup with laboratory tests and 6(1):e1002957. https://doi. org/10.37029/jcas.v6i1.281 imaging was diagnosed with HH with secondary pulmonary haemosiderosis. Copyright: © 2020 Jehangir, The patient is receiving twice weekly phlebotomies and has had an overall et al. This is an open access improvement in his symptoms. Practical Implications: The presentation article distributed under the of haemochromatosis can vary widely depending on the severity of iron terms of the Creative Commons Attribution License, which overload and the presence of conditions that predispose organ dysfunction. permits unrestricted use, Pulmonary haemosiderosis is a very rare manifestation of HH. This report distribution, and reproduction illustrates the various manifestations of this disease and provides insight in any medium, provided the into this rare presentation to improve the diagnosis of this disease. original author and source are credited. Key words: Dyspnoea, ferritins, haemochromatosis protein, Nill. Funding: haemochromatosis, haemosiderosis, mutation Competing interests: Nill.

Introduction (C282Y) in the HFE protein account for 82–90% of the clinical diagnosis of HH among Northern Hereditary haemochromatosis (HH) is an autosomal Europeans descendants.[2] Elevated serum ferritin recessive condition of dysregulated iron absorption and transferrin saturation (TSAT) occur more that may lead to an overload of total body iron with associated secondary tissue damage. The genetic frequently in males with C282Y homozygosity than [3-5] prevalence of this disorder is 0.4% in Northern females with the same amino acid substitution. Europeans; however, it has a much lower clinical European Association for the Study of the Liver prevalence.[1] Individuals with a homozygous defines HH as C282Y homozygosity and increased substitution of tyrosine for cysteine at position 282 body iron stores with or without clinical symptoms.[1]

Journal Of Cancer & Allied Specialties 1 J Cancer Allied Spec 2020;6(1):2 Case Report

Iron accumulation associated with HH may present and light weights without limitation. He endorsed in a variety of ways. Elevated serum alanine having fatigue and numbness and tingling in his aminotransferase levels indicating that hepatic hands and feet. He denied any other joint arthritis dysfunction is an early manifestation of this disease or darkening of the skin. He had no family history and may progress to cirrhosis and hepatocellular of iron overload and had no offspring. He was a carcinoma.[6,7] Iron may accumulate in the skin, former smoker and quit 1 week before the visit. leading to pigmentation as well as in endocrine He denied any alcohol consumption. His physical organs resulting in hypothyroidism, diabetes mellitus examination was completely benign. and hypogonadism.[8,9] In a severely iron overloaded state, cardiomyopathy may occur resulting in The blood haemochromatosis human homeostatic arrhythmias and heart failure.[10] Here, we describe HH iron regulator protein (HFE) gene analysis showed presenting with pulmonary haemosiderosis which is a rare presenting manifestation of this disease.

Case Report

A 49-year-old White male with no significant medical history or family history of iron overload was referred to haematology oncology for further evaluation of an elevated ferritin. The patient had not seen a medical provider for many years before a recent visit to an urgent care clinic for fatigue and left-sided face and left extremity paresthesia. On further workup including possible Vitamin B12 deficiency, he was found to have elevated haemoglobin of 17.6 g/dl, a ferritin level above 1300 ng/mL with a normal Vitamin B12 level, Figure 1: Chest X-ray showing fine reticular nodular white blood cell and platelet counts. A referral to pattern throughout the entirety of both lungs concerning haematology oncology department was placed. for pulmonary haemosiderosis

Four weeks after the urgent care visit, the patient presented to the emergency room with episodes of shortness of breath and chest pain. His chest X-ray showed fine reticular nodular pattern throughout the entirety of both lungs concerning for pulmonary haemosiderosis [Figure 1]. His electrolytes and liver function test were within normal limits. His workup showed normal Vitamin B12 levels and an elevated ferritin level of 1913 ng/mL. He denied any major issues or problems. On further workup at the haematology clinic, he specifically denied any history of diabetes, chest tenderness, joint pain, shortness of breath, cough, haemoptysis, history of prior lung disease, frequent respiratory illnesses, fever, chills, night sweats and gastro- Figure 2: Computed tomography chest showing diffuse oesophageal reflux disease. Before diagnosis, he reticular nodular opacities consistent with pulmonary was going to the gym regularly using the treadmill haemosiderosis

Journal Of Cancer & Allied Specialties 2 J Cancer Allied Spec 2020;6(1):3 Case Report two copies of the C282Y mutation. This result can per dry liver weight was approximately 29 mg/g take place in patients with HH. However, it does (normal is <1.8 mg/g) [Figure 3]. not confirm a diagnosis or predisposition to the development of HH. Computed tomography Diagnosis and Management (CT) chest showed diffuse reticular nodular Differential included interstitial lung disease opacities which are consistent with pulmonary haemosiderosis[11] [Figure 2]. Likewise, the patient due to his smoking history as well as pulmonary underwent FerriScan (Resonance Health, Burswood, haemosiderosis. Given the elevated ferritin, two Western Australia, Australia) which showed no focal copies of the C282Y mutation and the imaging abnormality on non-contrast sequences and marked results, the patient was diagnosed with HH with T2 hypointensity of the liver which is consistent with secondary pulmonary haemosiderosis. He was iron deposition. FerriScan transverse relaxation rate started on a weekly phlebotomy schedule for the shows that TSAT was >45% and his liver iron content goal ferritin of 50 ng/mL, while holding phlebotomy if haematocrit reached 33%. During follow-up, a laboratory test showed a ferritin of 1223 ng/mL and haemoglobin of 13.4 g/dl. The patient was placed on twice weekly phlebotomy (500 ml) with oral fluid replacement and a course of prednisone 40 mg daily for 2 weeks, tapered down to 30 mg for 2 weeks and then to 20 mg daily, as well as a prophylaxis sulfamethoxazole/trimethoprim (800/160 mg tablet) every alternate day, 3 days a week. At 3-month follow-up, he reported an improvement in his fatigue. A repeat chest CT was conducted after 5 months of prior CT [Figure 4] and it showed minimal residual abnormality with a reported improvement in diffuse reticular nodular opacities.

Figure 3: Computed tomography (CT) chest performed Discussion 5 months after initial CT scan with minimal residual abnormality with a reported improvement in diffuse The presentation of HH can vary depending reticular nodular opacities on the severity of iron overload, the organ

Figure 4: Ferri Scan shows that the transverse relaxation rate transferrin saturation was >45% and his liver iron content per dry liver weight was approximately 29 mg/g (normal is <1.8 mg/g)

Journal Of Cancer & Allied Specialties 3 J Cancer Allied Spec 2020;6(1):4 Case Report involved and the presence of other conditions Here, we report a case of a 49-year-old male with an that may lead to organ dysfunction. Before our elevated ferritin level who presented with shortness understanding of the genetics of HH and the of breath and chest pain. His symptoms were likely HFE gene, the majority of patients presented due to haemosiderosis secondary to HH which with symptoms caused by iron accumulation. was confirmed with iron studies, genetic testing Analysis of a population of patients from 1959 and FerriScan magnetic resonance imaging. With to 1992 with haemochromatosis concluded that this report, we hope to illuminate a rare possible 75% of individuals presented with abnormalities manifestation of HH and encourage further research in liver function tests, 74% of patients had to assess if more patients with HH have pulmonary weakness and lethargy, 70% of patients presented findings. with hyperpigmentation, 48% of patients had concurrent diabetes mellitus, 44% of patients Conflicts of Interest had arthralgia, 31% of patients presented with The authors declare that they have no conflicts of electrocardiogram abnormalities and 45% of interest. male patients had impotence at the time of presentation.[12] While there is a wide array References of possible manifestations of HH, pulmonary 1. Pietrangelo A, Deugnier Y. EASL clinical practice haemosiderosis is rarely reported. guidelines for HFE hemochromatosis. J Hepatol 2007;53:3-22. At present, routine availability of iron studies and 2. Adams P, Barton J. Haemochromatosis. Lancet genetic testing has led to earlier diagnosis and less 2007;370:1855-60. severe progression of the disease. A more recent 3. Olynyk J, Cullen D. A population-based study of the study found that 76% of individuals who were clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:1708-8. diagnosed with HH were asymptomatic at the time 4. Andersen R. Hemochromatosis mutations in the [13] of testing. Pulmonary haemosiderosis is not a general population: Iron overload progression rate. common presenting sign of HH and is more often Blood 2004;103:2914-9. a result of recurrent episodes of diffuse alveolar 5. Delatycki M, Allen K, Nisselle A, Collins V, Metcalfe S, haemorrhage. This may be due to infection, du Sart D, et al. Use of community genetic screening to prevent HFE-associated hereditary rheumatic disease, medications or inhalation haemochromatosis. Lancet 2005;366:314-6. exposures; however, the aetiology of pulmonary 6. Kowdley K. Iron, hemochromatosis, and haemosiderosis is often unknown.[14] hepatocellular carcinoma. Gastroenterology 2004;127:S79-86. Pulmonary haemosiderosis secondary to 7. Crownover B, Covey C. Hereditary Hemochromatosis; 2019. Available from: https://www.aafp.org/ haemochromatosis has been reported once afp/2013/0201/p183.html. [Last accessed on previously in the Spanish medical literature in 2019 Sep 01]. Archivos de Bronconeumologia in 1995.[15] In this 8. McNeil L, McKee L, Lorber D, Rabin D. The endocrine case report, authors performed a transbronchial manifestations of hemochromatosis. Am J Med Sci biopsy, which confirmed iron deposits in alveolar 1983;285:7-13. 9. Utzschneider K, Kowdley K. Hereditary macrophages. Pathognomic feature of pulmonary hemochromatosis and diabetes mellitus: Implications haemosiderosis is lung biopsy, which should be for clinical practice. Nat Rev Endocrinol 2010;6:26-33. suggestive for the presence of haemosiderin-laden 10. Gulati V, Harikrishnan P, Palaniswamy C, Aronow W, macrophages. However, this was no conducted in Jain D, Frishman W. Cardiac involvement in the present case report due to genetic evidence hemochromatosis. Cardiol Rev 2014;22:56-68. 11. Kamienska E, Urasinski T, Gawlikowska-Sroka A, of HH, the imaging findings and the overall Glura B, Pogorzelski A. Idiopathic pulmonary improvement in symptoms following repeated hemosiderosis in a 9-year-old girl. Eur J Med Res therapeutic phlebotomy. 2009;14 Suppl 4:112-5.

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12. Niederau C, Strohmeyer G, Stremmel W. Epidemiology, interstitial disease due to hemochromatosis as a clinical spectrum and prognosis of hemochromatosis. presenting sign of disease. Arch Bronconeumol Adv Exp Med Bio 1994;356:293-302. 1995;31:9. 13. Cherfane C, Hollenbeck R, Go J, Brown K. Hereditary hemochromatosis: Missed diagnosis or misdiagnosis? Am J Med 2013;126:1010-5. Authorship Contributions 14. Ioachimescu O, Kotch A, Stoller J. Idiopathic pulmonary hemosiderosis in adults. Clin Pulm Med Conceived and designed the analysis: WJ, ADK, 2005;12:16-25. ERU; Collected the data: N/A; Performed the 15. Pereiro A, Garcia G, Muniz M, Campa A. Pulmonary analysis: N/A; Wrote the paper: WJ, ADK, ERU.

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